Angiogenesis, the development of new blood vessels, is a highly regulated and essential process of endothelial cell growth. Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as “angiogenic diseases”) are driven by persistent unregulated angiogenesis. Unregulated, angiogenesis may either cause a particular disease directly or exascerbate an existing pathological condition. For example, ocular neovacularization has been implicated as the most common cause of blindness and dominates approximately 20 eye diseases. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also angiogenesis-dependent (Folkman, J., Cancer Research, 46: 467473 (1986), Folkman, J., Journal of the National Cancer Institute, 82: 4-6 (1989)).
Much research has been performed to identify anti-antiogenic molecules. One angiogenic molecule of particular interest is plasminogen. Of particular interest is the kringle 5 region of plasminogen and various peptides within the kringle 5 region. Both plasminogen and the kringle 5 region of plasminogen have been shown to interfere with the angiogenic process are thus known as anti-angiogenic peptides.
While useful, kringle 5 peptides, like other peptides, suffer from rapid kidney excretion, liver metabolism, and decomposition from endogeneous peptidases leading to very short plasma half-lives thereby reducing their usefulness as anti-angiogenic agents. As a result of their short half lives, peptides such as kringle 5 require constant infusion to reach adequate plasma levels sufficient for efficient therapy.
As a result, there is a need for long lasting anti-angiogenic peptides such as kringle 5. Such long lasting peptides would be useful in treating angiogenesis related diseases in mammals.